The present invention relates to an anilide derivative or a salt thereof having antagonistic activity on MCP-1 (monocyte chemoattractant protein-1) receptor, production method and use thereof.
MCP-1 is known to be a monocyte chemotactic factor relating to inflammatory diseases, and belongs to CC chemokine sub-family. MCP-1 is found to express not only from monocyte but also from cardiac muscle cell, blood vessel endothelial cell, fibroblast, chondrocyte, smooth muscle cell, mesangial cell, aveolar cell, T lymphocyte, macrophage, etc. in various pathosis (specifically, angiostenosis, arteriosclerosis, rheumatic arthritis, diabetic microangiopathy, granulomatous inflammation (tuberculosis, sarcoidosis, etc.), solid cancer, diastolic cardiomyopathy (chronic heart failure, etc.), glomerulonephritis, etc.), and MCP-1 deeply relate to crisis and progression these pathosis. Therefore, MCP-1 receptor antagonists are used as a medicament for the treatment and prophylaxis of these pathosis.
So far, there have been only a little reports on low molecule compounds having antagonistic activity on MCP-1 receptor. For example, it is disclosed that aryloxy-propanolamine derivatives being active as xcex2-blocker show weak inhibitory activity on MCP-1 binding to its receptor in JP-A-25756/1995 and that phenylethanolamine derivatives having sympathetic activity and sympatholytic activity show weak inhibitory activity on MCP-1 binding to its receptor in JP-A-25757/1995.
On the other hand, phosphonic acid derivatives having osteogenesis activity is disclosed in JP-A-73476/1996 but there is no description on MCP-1 receptor antagonistic activity.
The present invention is to provide a new anilide derivative or a salt thereof having antagonistic activity on MCP-1 receptor and therapeutic and prophylactic effect on cardiac infarction, myocarditis, cardiomyopathy, chronic heart failure, restenosis after angioplasty, disorder after reperfusion in lung and heart, inflammatory diseases (e.g. arteriosclerosis, arteriosclerosis after heart transplantation, (chronic) rheumatic arthritis, nephritis, etc.), rejection after organ transplantation, fibroid lung, renal insufficiency, diabetic diseases (e.g. diabetes, diabetic nephropathy, diabetic complication, diabetic retinopathy, diabetic retinitis, diabetic microangiopathy, etc.), tumor (e.g. bladder cancer, breast carcinoma, cervical carcinoma, chronic lymphocytic leukemia, chronic myelocytic leukemia, colon carcinoma, multiple myeloma, malignant myeloma, prostatic cancer, lung cancer, stomach cancer, Hodgkin""s disease, etc.) infectious diseases (e.g. tuberculosis, invasive staphylococcia, etc.), etc.; production method and use thereof.
The present inventors diligently made extensive studies on compounds having MCP-1 receptor antagonistic activity and, as a result, they found that an anilide derivative of the following formula (I) or a salt thereof [hereinafter, referred to as Compound (I)] unexpectedly possesses potent MCP-1 receptor antagonistic activity and clinically desirable pharmaceutical effect. Based on the finding, the present invention was accomplished.
More specifically, the present invention relates to
(1) a compound of the formula: 
wherein R1 is an optionally substituted 5- to 6-membered ring, W is a divalent group of the formula: 
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, the ring B is an optionally substituted 5- to 7-membered ring, Z is a chemical bond or a divalent group, R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5 and R6 are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R5 and R6 may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof;
(2) a compound of the above (1) wherein R1 is benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine piperazine, morpholine, thiomorpholine or tetrahydropyran, each of which may be substituted;
(3) a compound of the above (1), wherein R1 is an optionally substituted benzene;
(4) a compound of the above (1), wherein the ring A is furan, thiophene, pyrrole, pyridine or benzene, each of which may be substituted;
(5) a compound of the above (1), wherein the ring A is an optionally substituted benzene;
(6) a compound of the above (1), wherein W is a group of the formula: 
wherein each symbol is as defined in the above (1);
(7) a compound of the above (1), wherein W is a group of the formula: 
wherein each symbol is as defined in the above (1);
(8) a compound of the above (7), wherein the ring B is a 5- to 7-membered ring group of the formula: 
wherein Y is xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x94(Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and m is an integer of 0-2), xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Nxe2x95x90CHxe2x80x94), which may have a substituent at any possible position;
(9) a compound of the above (8), wherein Y is xe2x80x94Yxe2x80x2xe2x80x94(CH2)2xe2x80x94(Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94);
(10) a compound of the above (8), wherein Y is xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94 or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94;
(11) a compound of the above (10), wherein the ring A is an optionally substituted benzene;
(12) a compound of the above (1), wherein Z is an optionally substituted C1-3 alkylene:
(13) a compound of the above (1), wherein Z is a divalent group of the formula: xe2x80x94Zxe2x80x2xe2x80x94(CH2)nxe2x80x94(Zxe2x80x2 is xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, and n is an integer of 0-2) in which an optional methylene group may be substituted;
(14) a compound of the above (1), wherein Z is methylene;
(15) a compound of the above (1), wherein Z is substituted at para position of the benzene ring;
(16) a compound of the above (1), wherein R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, or (3) a group of the formula: 
wherein R5 and R6 are independently an optionally substituted hydrocarbon group, and R5 and R6 may bind to each other to form a cyclic group together with the adjacent phosphorus atom;
(17) a compound of the formula: 
wherein Xxe2x88x92 is an anion;
(18) a compound of the above (17), wherein X is a halogen atom;
(19) a compound selected from the class consisting of N-methyl-N-[4-[[[2xe2x80x94(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-piperidinium iodide, N-methyl-N-[4-[[[7xe2x80x94(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidinium iodide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-7xe2x80x94(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide, N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]-phenyl]-7xe2x80x94(4-morpholinophenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide, 7xe2x80x94(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxmide, N,N-dimethyl-N-[4-[[[2xe2x80x94(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammonium iodide and N-methyl-N-[4-[[[7xe2x80x94(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidinium iodide,
or a salt thereof;
(20) a method for producing a compound of the formula: 
wherein each symbol is as defined above (1) or a salt thereof, which comprises subjecting a compound of the formula:
R1xe2x80x94Wxe2x80x94COOHxe2x80x83xe2x80x83(II)
wherein each symbol is as defined above (1), a salt or a reactive derivative thereof to condensation reaction with a compound of the formula: 
wherein Z is as defined above (1) and R2xe2x80x2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5 and R6 are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R1 and R may bind to each other to form a cyclic group together with the adjacent phosphorus atom, the above groups (1)-(4) being optionally protected, or a salt thereof, and, if desired, subjecting the obtained product to deprotection, oxidation, reduction and/or ammoniumation;
(21) 3xe2x80x94(4-methylphenyl)-8,9-dihydro-7H-benzocycloheptene-6-carboxylic acid or a salt thereof;
(22) a pharmaceutical composition comprising a compound of the above (1) or a salt thereof;
(23) a composition of the above (22), which is for antagonizing MCP-1 receptor;
(24) a composition of the above (22), which is for the treatment or prophylaxis of cardiac infarction or myocarditis;
(25) a pharmaceutical composition for antagonizing MCP-1 receptor (or a pharmaceutical composition for inhibiting binding of MCP-1 (a ligand) to MCP-1 receptor or a pharmaceutical composition for antagonizing binding of MCP-1 to its receptor), which comprises a compound of the formula: 
wherein R1 is an optionally substituted 5- to 6-membered ring, W is a divalent group of the formula: 
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, the ring B is an optionally substituted 5- to 7-membered ring, Z is a chemical bond or a divalent group, R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5xe2x80x2and R6xe2x80x2 are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5xe2x80x2 and R6xe2x80x2 may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof;
(26)a method for antagonizing MCP-1 receptor which comprises administering to a mammal in need thereof an effective amount of a compound of the formula: 
wherein R1 is an optionally substituted 5- to 6-membered ring:
W is a divalent group of the formula: 
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, and the ring B is an optionally substituted 5- to 7-membered ring; Z is a chemical bond or a divalent group; R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5xe2x80x2 and R6xe2x80x2 are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5xe2x80x2 and R6xe2x80x2 may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof;
(27) a method for antagonizing MCP-1 receptor which comprises administering to a mammal in need thereof an effective amount of a compound of the above (1) or a salt thereof;
(28) use of a compound of the formula: 
wherein R1 is an optionally substituted 5- to 6-membered ring;
W is a divalent group of the formula: 
wherein the ring A is an optionally substituted 5- to 6-membered aromatic ring, X is an optionally substituted carbon atom, an optionally substituted nitrogen atom, sulfur atom or oxygen atom, and the ring B is an optionally substituted 5- to 7-membered ring; Z is a chemical bond or a divalent group; R2 is (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium,
(2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary;ammonium, (3) a group binding through a sulfur atom or (4) a group of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5xe2x80x2 and R6xe2x80x2 are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5xe2x80x2 and R6xe2x80x2 may bind to each other to form a cyclic group together with the adjacent phosphorus atom, or a salt thereof, for the manufacture of a medicament for antagonizing MCP-1 receptor;
(29) use of a compound of the above (1) or a salt thereof for the manufacture of a medicament for antagonizing MCP-1 receptor; etc.
In the above formula (I), examples of the xe2x80x9c5- to 6-membered ringxe2x80x9d of the xe2x80x9coptionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 include a 6-membered aromatic hydrocarbon such as benzene, etc.; a 5- to 6-membered aliphatic hydrocarbon such as cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentanediene, cyclohexanediene, etc.; 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; 5- to 6-membered non-aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran, etc.; etc. Among others, benzene, furan, thiophene, pyridine, cyclopentane, cyclohexane, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyran (preferably, 6-membered ring), etc. are preferable, and in particular, benzene is preferable.
Example of the xe2x80x9csubstituentsxe2x80x9d which the xe2x80x9c5- to 6-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 may have include halogen atom, nitro, cyano, an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted hydroxy group, an optionally substituted thiol group wherein a sulfur atom may be optionally oxidized to form a sulfinyl group or a sulfonyl group, an optionally substituted amino group, an optionally substituted acyl, an optionally esterified carboxyl group, an optionally substituted aromatic group, etc.
Examples of the halogen as the substituents for R1 include fluorine, chlorine, bromine, iodine, etc. Among others, fluorine and chlorine are preferable.
Examples of the alkyl in the optionally substituted alkyl as the substituents for R1 include a straight or branched C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., and preferably lower (C1-6) alkyl.
Examples of the substituents in the optionally substituted alkyl include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the cycloalkyl in the optionally substituted cycloalkyl as the substituents for R1 include C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
Examples of the substituents in the optionally substituted cycloalkyl include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted hydroxy group as the substituents for R1 include
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2-6) alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(6) an optionally substituted acyl (e.g. C2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(7) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc.
Examples of the substituents which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl and (7) optionally substituted aryl may have include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted thiol group as the substituents for R1 are similar to the above-described substituents in the optionally substituted hydroxy group as the substituents for R1, and among others,
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(4) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc. are preferable.
Examples of the substituents which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl and (4) optionally substituted aryl may have include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the substituents in the optionally substituted amino group as the substituents for R1 are similar to the above-described substituents in the optionally substituted hydroxy group as the substituents for R1, and examples of the optionally substituted amino group as the substituents for R1 include an amino group which may have one to two substituents selected from the above-described substituents in the optionally substituted hydroxy group as the substituents for R1, etc. Among others, as the substituents in the optionally substituted amino group as the substituents for R1,
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2-6) alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted acyl (e.g. C2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(6) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc. are preferable.
Examples of the substituents, which each of the above-described (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl and (6) optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
The substituents in the optionally substituted amino group as the substituents for R1 may bind to each other to form a cyclic amino group (e.g. 5- to 6-membered cyclic amino, etc. such as tetrahydropyrrole, piperazine, piperidine, morpholine, thiomorpholine, pyrrole, imidazole, etc.). Said cyclic amino group may have a substituent, and examples of the substituents include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the optionally substituted acyl as the substituents for R1 include a carbonyl group or a sulfonyl group binding to
(1) hydrogen;
(2) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e. g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl, 3-hexenyl, etc., preferably lower (C2-6) alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(6) an optionally substituted 5- to 6-membered monocyclic aromatic group (e.g. phenyl, pyridyl, etc.); etc.
Examples of the acyl include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, nicotinoyl, methanesulfonyl, ethanesulfonyl, etc.
Examples of the substituents, which the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl and (6) optionally substituted 5- to 6-membered monocyclic aromatic group may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the optionally esterified carboxyl group as the substituents for R1 include a carbonyloxy group binding to
(1) hydrogen;
(2) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(3) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(4) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower (C2-6) alkenyl, etc.);
(5) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(6) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc., and preferably carboxyl, lower (C1-6) alkoxycarbonyl, aryloxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, phenoxycarbonyl, naphthoxycarbonyl, etc.), etc.
Examples of the substituents, which the above-mentioned (2) optionally substituted alkyl, (3) optionally substituted cycloalkyl, (4) optionally substituted alkenyl, (5) optionally substituted cycloalkenyl and (6) optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4, alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the aromatic group in the optionally substituted aromatic group as the substituents for R1 include 5- to 6-membered homocyclic or heterocyclic ring aromatic ring, etc. such as phenyl, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, etc.
Examples of the substituents for these aromatic group include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
The number of the above-mentioned substituents for R1 is 1-4 (preferably 1-2) and they may be same or different and present at any possible position on the ring represented by R1. When two or more substituents. are present on the 5- to 6-membered ring in the xe2x80x9can optionally substituted 5- to 6-membered ringxe2x80x9d represented by R1, two substituents among them may bind to each other to form a lower (C1-6) alkylene (e.g. trimethylene, tetramethylene, etc.), a lower (C1-6) alkyleneoxy (e.g. xe2x80x94CH2xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, etc.), a lower (C1-6) alkylenedioxy (e.g. xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, etc.), a lower (C2-6) alkenylene (e.g. xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, etc.), a lower (C4-6) alkadienylene (e.g. xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, etc.), etc.
Preferred examples of the xe2x80x9csubstituentsxe2x80x9d, which the xe2x80x9c5- to 6-membered ringxe2x80x9d in the xe2x80x9can optionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 may have, include an optionally halogenated lower (C1-4) alkyl (e.g. methyl, ethyl, t-butyl, trifluoromethyl, etc.), an optionally halogenated lower (C1-4) alkoxy (e.g. methoxy, ethoxy, t-butoxy, trifluoromethoxy, etc.), halogen (e.g. fluorine, chlorine, etc.), nitro, cyano, an amino group optionally substituted with 1-2 lower (C1-4) alkyl groups (e.g. amino, methylamino, dimethylamino, etc.), 5- to 6-membered cyclic amino (e.g. 1-pyrrolidinyl, 1-piperazinyl, 1-piperidinyl, 4-morpholino, 4-thiomorpholin, 1-imidazolyl, 4-tetrahydropyranyl, etc.), etc., and when R1 is a benzene, the xe2x80x9csubstituentxe2x80x9d is preferably present at para position.
In the above formula (I), examples of the xe2x80x9c5- to 6-membered aromatic ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered aromatic ringxe2x80x9d represented by A include 6-membered aromatic hydrocarbon such as benzene, etc.; 5- to 6-membered aromatic heterocyclic ring containing 1 to 3 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; etc. Among others, benzene, furan, thiophene, pyridine (preferably, 6-membered ring) etc. are preferable, and in particular benzene is preferable.
Examples of the xe2x80x9csubstituentsxe2x80x9d, which the xe2x80x9c5- to 6-membered aromatic ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered aromatic ringxe2x80x9d represented by A may have, are similar to the xe2x80x9csubstituentsxe2x80x9d which the xe2x80x9c5- to 6-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 may have. The number of said substituents for the ring A is 1-4 (preferably 1-2), and they may be same or different and present at any possible position (e.g. the position of the group X and the other positions) on the ring represented by A.
In the above formula (I), a group of the formula: 
binds to adjacent groups in the following manner: 
In the above formula (I), examples of the xe2x80x9c5- to 7-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 7-membered ringxe2x80x9d represented by B include a 5- to 7-membered ring group of the formula: 
which may have a substituent at any possible position, etc.
In the above formula, the divalent group represented by Y may be any divalent group as far as the ring B forms an optionally substituted 5- to 7-membered ring, and preferred examples of the divalent groups include
(1) xe2x80x94(CH2)a1xe2x80x94Oxe2x80x94(CH2)a2xe2x80x94(a1 and a2 are same or different and 0, 1 or 2, provided that the sum of a1 and a2 is 2 or less), xe2x80x94Oxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94Oxe2x80x94;
(2) xe2x80x94(CH2)b1xe2x80x94Sxe2x80x94(CH2)b2xe2x80x94(b1 and b2 are same or different and 0, 1 or 2, provided that the sum of b1 and b2 is 2 or less), xe2x80x94Sxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94Sxe2x80x94;
(3) xe2x80x94(CH2)d1xe2x80x94(d1 is 1, 2 or 3), xe2x80x94CH2xe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94;
(4) xe2x80x94(CH2)e1xe2x80x94NHxe2x80x94(CH2)e2xe2x80x94(e1 and e2 are same or different and 0, 1 or 2, provided that the sum of e1 and e2 is 2 or less), xe2x80x94NHxe2x80x94(CHxe2x95x90CH)xe2x80x94, xe2x80x94(CHxe2x95x90CH)xe2x80x94NHxe2x80x94, xe2x80x94(CH2)e6xe2x80x94(Nxe2x95x90CH)xe2x80x94(CH2)e7xe2x80x94, xe2x80x94(CH2)e7xe2x80x94(CHxe2x95x90N)xe2x80x94(CH2)e6xe2x80x94(one of e6 and e7 is 0, and the other is 1), xe2x80x94(CH2)e8xe2x80x94(Nxe2x95x90N)xe2x80x94(CH2)e9xe2x80x94(one of e8 and e9 is 0, and the other is 1); etc. More preferred examples of the divalent groups include xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94 (in which each of the above formulas represent that it binds to the ring A through its left chemical bond), etc.
The divalent group may have a substituent. Examples of the substituent include those for the xe2x80x9c5- to 6-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 and an oxo group, etc. Among others, a lower (C1-3) alkyl (e.g. methyl, ethyl, propyl, etc.), a phenyl group, an oxo group, a hydroxy group, etc. are preferable. In addition, the divalent group may be xe2x80x94Oxe2x80x94C(O)xe2x80x94 (in which each of the above formulas represent that it binds to the ring A through its left chemical bond), etc. The number of the substituents are preferably 1 to 4 (preferably, 1-2), and they may be same or different and bind to the divalent group at any possible position.
As the divalent group represented by Y, a group of the formula: xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x94(Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and m is an integer of 0-2), xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94(CH2)mxe2x80x94Yxe2x80x2, (Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and m is an integer of 0-2), xe2x80x94CHxe2x95x90Nxe2x80x94 (in which each of the above formulas represent that it binds to the ring A through its left chemical bond), etc. is preferable. Among others, a group of the formula: xe2x80x94Yxe2x80x2xe2x80x94(CH2)mxe2x80x94(Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94, and m is an integer of 0-2), xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94 (in which each of the above formulas represent that it binds to the ring A through its left chemical bond), etc. is preferable. In particular, Y is preferably a group of the formula: xe2x80x94Yxe2x80x2xe2x80x94(CH2)2xe2x80x94(Yxe2x80x2 is xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94CH2xe2x80x94 (preferably xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94, more preferably xe2x80x94Oxe2x80x94 or xe2x80x94CH2xe2x80x94)) in which the formula binds to the ring A through its left chemical bond, etc.; and the ring B is preferably a 7-membered ring. As the divalent group represented by Y, a group of the formula: xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94 or xe2x80x94Oxe2x80x94(CH2)2xe2x80x94 is preferable.
Examples of the xe2x80x9csubstituentsxe2x80x9d, which the xe2x80x9c5- to 7-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 7-membered ringxe2x80x9d represented by B may have, include those for the xe2x80x9c5- to 6-membered ringxe2x80x9d in the xe2x80x9coptionally substituted 5- to 6-membered ringxe2x80x9d represented by R1 and an oxo group, etc. The number of the substituents are preferably 1 to 4 (preferably, 1-2), and they may be same or different and bind to the divalent group at any possible position.
In a group of the formula: 
represented by W, a carbon atom at the position a is preferably unsubstituted.
In the above formula (I), examples of the divalent group represented by Z include an optionally substituted divalent group whose straight chain is constituted by 1 to 4 carbon atoms (e.g. C1-4 alkylene, C2-4 alkenylene, etc., preferably C1-3 alkylene, more preferably methylene), etc. The group Z may be bound to any possible position of the benzene ring, and preferably to para position of the benzene ring.
The divalent group represented by Z may be any divalent group whose straight chain is constituted by 1 to 4 atoms and exemplified by an alkylene chain of the formula: xe2x80x94(CH2)k1xe2x80x94(k1 is an integer of 1-4), an alkenylene chain of the formula: xe2x80x94(CH2)k2xe2x80x94(CHxe2x95x90CH)xe2x80x94(CH2)k3xe2x80x94(k2 and k3 are same or different and 0, 1 or 2, provided that the sum of k2 and k3 is 2 or less), etc.
Examples of the substituent for the divalent group represented by Z include any one which is capable of binding to the straight chain of the divalent group, and preferably C1-6 lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc.), lower (C3-7) cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), an optionally esterified phosphono group, an optionally esterified carboxyl group, hydroxy group, oxo, etc., and more preferably C1-6 lower alkyl (preferably C1-3 alkyl). hydroxy group, oxo, etc.
Examples of the optionally esterified phosphono group include a group of the formula: P(O)(OR7)(OR8) wherein R7 and R8 are independently hydrogen, a C1-6 alkyl group or a C3-7 cycloalkyl group, and R7 and R8 may bind to each other to form a 5- to 7-membered ring.
In the above formula, examples of the C1-6 alkyl group represented by R7 and R8 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and examples of the C3-7 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. Among other, a straight C1-6 lower alkyl is preferable and C1-3 lower alkyl is more preferable. The groups R7 and R8 may be same or different, and preferably the groups R7 and R8 are same. When R7 and R8 may bind to each other to form a 5- to 7-membered ring, the groups R7 and R8 bind to each other to represent a straight C2-4 alkylene chain of the formula: xe2x80x94(CH2)2xe2x80x94, xe2x80x94(CH2)3xe2x80x94, xe2x80x94(CH2)4xe2x80x94, etc. Said chain may have a substituent, and examples of the substituent include hydroxy group, halogen, etc.
Examples of the optionally esterified carboxyl group include a carboxyl group and an ester group formed by binding a carboxyl group to a C1-6 alkyl group or a C3-7 cycloalkyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.).
As the divalent group represented by Z, an optionally substituted C1-3 alkylene is preferable, and C1-3 alkylene which may be substituted by C1-3 alkyl, hydroxy group or oxo is more preferable.
Among others, as the divalent group represented by Z, a group of the formula: xe2x80x94Zxe2x80x2xe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)nxe2x80x94Zxe2x80x2, (Zxe2x80x2 is xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, and n is an integer of 0-2) in which each of the above formulas represent that it binds to the benzene ring through its left chemical bond and each of the methylene groups may be substituted by 1-2 same or different substituents is preferable, a group of the formula; xe2x80x94Zxe2x80x2xe2x80x94(CH2)n, (Zxe2x80x2 is xe2x80x94CH(OH)xe2x80x94, xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, and n is an integer of 0-2 (preferably, n is 0)) in which the formula binds to the benzene ring through its left chemical bond and each of the methylene groups may be substituted by 1-2 same or different substituents is more preferable, and methylene is particularly preferable.
In the above-mentioned formula (I), examples of the xe2x80x9camino groupxe2x80x9d in the xe2x80x9coptionally substituted amino group in which a nitrogen atom may form a quaternary ammoniumxe2x80x9d represented by R2 include an amino group which may have 1-2 substituents, an amino group having 3 substituents wherein the nitrogen atom forms a quaternary ammonium, etc. When the number of the substituents on the nitrogen atom is 2 or more, these substituents may be same or different. When the total number of the substituents and hydrogen atoms on the nitrogen atom is 3, the xe2x80x9camino groupxe2x80x9d represented by R2 may be any type of an amino group represented by the formula: xe2x80x94N+R3, xe2x80x94N+R2Rxe2x80x2 or xe2x80x94N+RRxe2x80x2Rxe2x80x3 (R, Rxe2x80x2 and Rxe2x80x3 are independently a hydrogen atom or a substituent). Examples of the counter anion of the amino group wherein the nitrogen atom forms a quaternary ammonium include an anion of a halogen atom (e.g. Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.) etc., and also an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid. oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc., etc. Among others, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc. are preferable.
Examples of the substituents for said amino group include
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower.(C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-8 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), provided that
(2-1) said cycloalkyl may contain one hetero-atom selected from a sulfur atom, an oxygen atom and a nitrogen atom to form oxirane, thiorane, aziridine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1-oxide, piperidine, etc. (preferably, 6-membered ring such as tetrahydropyran, tetrahydrothiopyran, piperidine, etc.) and these groups preferably bind to the amino group at their 3- or 4-position (preferably, 4-position), that
(2-2) said cycloalkyl may be fused with a benzene ring to form indane, tetrahydronaphthalene, etc. (preferably, indane, etc.), and that
(2-3) said cycloalkyl may have a bridging comprising a straight chain constituted by 1-2 carbon atoms to form a bridged hydrocarbon residue such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2 ]nonyl, etc., preferably, a cyclohexyl group, etc. having a bridging comprising a straight chain constituted by 1-2 carbon atoms, and more preferably bicyclo[2.2.1]heptyl, etc.;
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower (C2-6)alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(6) an optionally substituted acyl (e.g. C2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(7) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.);
(8) an optionally substituted heterocyclic ring group (e.g. 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as furan, thiophene, pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; 5- to 6-membered non-aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from oxygen atom, sulfur atom and nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, etc.; etc.; preferably 5- to 6-membered non-aromatic heterocyclic ring, etc.; more preferably 5- to 6-membered non-aromatic heterocyclic ring containing one hetero-atom, etc. such as tetrahydrofuran, piperidine, tetrahydropyran, tetrahydrothiopyran, etc.); etc.
Examples of the substituents, which the above-mentioned (1) optionally substituted. alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl, (7) optionally substituted aryl and (8) optionally substituted heterocyclic ring group may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated lower (C1-4) alkyl, an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C1-4 alkylenedioxy (e.g. xe2x80x94Oxe2x80x94CH2xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), phenyl-lower (C1-4) alkyl, C3-7 cycloalkyl, cyano, nitro, hydroxy group, thiol group, amino group, carboxyl group. lower (C1-4) alkoxy-carbonyl (preferably, halogen, an optionally halogenated lower (C1-4) alkyl, an optionally halogenated lower (C1-4) alkoxy, phenyl-lower (C1-4) alkyl, C3-7 cycloalkyl, cyano, hydroxy group, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula (I), preferred examples of the xe2x80x9coptionally substituted amino group in which a nitrogen atom may form a quaternary ammoniumxe2x80x9d represented by Rxe2x80x2 include an amino group which may have 1-3 substituents selected from
(1) a straight or branched lower (C1-6) alkyl which may have 1 to 3 substituents selected from halogen, cyano, hydroxy group or C3-7 cycloalkyl;
(2) a C5-8 cycloalkyl which may have 1 to 3 substituents selected from halogen, an optionally halogenated lower (C1-4) alkyl or phenyl-lower (C1-4) alkyl, which may contain one hetero-atom selected from a sulfur atom, an oxygen atom and a nitrogen atom, which may be fused with a benzene ring, and which may have a bridging comprising a straight chain constituted by 1-2 carbon atoms (e.g. cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidinyl, indanyl, tetrahydronaphthalenyl, bicyclo[2.2.1]heptyl, etc., each of which may be substituted);
(3) a phenyl-lower (C1-4 ) alkyl which may have 1 to 3 substituents selected from halogen, an optionally halogenated lower (C1-4) alkyl or an optionally halogenated lower (C1-4) alkoxy;
(4) a phenyl which may have 1 to 3 substituents selected from halogen, an optionally halogenated lower (C1-4) alkyl or an optionally halogenated lower (C1-4) alkoxy; and
(5) a 5- to 6-membered aromatic heterocyclic ring (e.g. furan, thiophene, pyrrole, pyridine, etc.) which may have 1 to 3 substituents selected from halogen, an optionally halogenated lower (C1-4) alkyl, an optionally halogenated lower (C1-4) alkoxy, an optionally halogenated lower (C1-4) alkoxy-lower (C1-4) alkoxy, phenyl-lower (C1-4) alkyl, cyano or hydroxy group.
In the above formula (I), examples of the xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d in the optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammoniumxe2x80x9d include a 5- to 6-membered aromatic heterocyclic ring which may contain 1 to 3 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than one nitrogen atom such as pyrrole, imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; 5-8 membered non-aromatic heterocyclic ring which may contain 1 to 3 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom other than one nitrogen atom such as pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, azacycloheptane, azacyclooctane (azocane), etc.; etc. These nitrogen-containing heterocyclic rings may have a bridging comprising a straight chain constituted by 1-2 carbon atoms to form a bridged nitrogen-containing heterocyclic ring azabicyclo[2.2.1]heptane, azabicyclo[2.2.2]octane (quinuclidine), etc. (preferably, piperidine having a bridging comprising a straight chain constituted by 1-2 carbon atoms, etc.).
Among the above-exemplified nitrogen-containing heterocyclic rings, pyridine, imidazole, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, azabicyclo[2.2.2]octane (preferably, a 6-membered ring) are preferable.
The nitrogen atom of said xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d may form a quaternary ammonium or may be oxidized. When the nitrogen atom of said xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d forms a quaternary ammonium, examples of the counter anion of the xe2x80x9cnitrogen-containing heterocyclic ring wherein the nitrogen atom forms a quaternary ammoniumxe2x80x9d include an anion of a halogen atom (e.g. Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.), etc., and also an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid. sulfuric acid, phosphoric acid, etc.; an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc. are preferable.
Said xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d may bind to the divalent group represented by Z through either a carbon atom or a nitrogen atom, and may be 2-pyridyl, 3-pyridyl, 2-piperidinyl, etc. which binds to the divalent group represented by Z through a carbon atoms. Preferably, the xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d binds to the divalent group represented by Z through a nitrogen atom, as exemplified by the following formulas: 
Examples of the substituents, which said xe2x80x9cnitrogen containing heterocyclic ringxe2x80x9d may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.) an optionally substituted lower (C1-4) alkyl, an optionally substituted lower (C1-4) alkoxy, an optionally substituted phenyl. an optionally substituted mono- or di-phenyl-lower (C1-4) alkyl, an optionally substituted C3-7 cycloalkyl, cyano, nitro, hydroxy group, thiol group, amino group, carboxyl group, lower (C1-4) alkoxy-carbonyl, lower (C1-4) alkanoyl, lower (C1-4) alkylsulfonyl. an optionally substituted heterocyclic ring group (e.g. 5- to 6-membered aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as furan, thiophene, pyrrole. imidazole, pyrazole, thiazole, oxazole, isothiazole, isoxazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazole, etc.; 5- to 6-membered non-aromatic heterocyclic ring containing 1 to 4 hetero-atoms consisting of 1 to 2 kinds of hetero-atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom such as tetrahydrofuran, tetrahydrothiophene, dithiolane, oxathiolane, pyrrolidine, pyrroline, imidazolidine, imidazoline, pyrazolidine, pyrazoline, piperidine, piperazine, oxazine, oxadiazine, thiazine, thiadiazine, morpholine, thiomorpholine, pyran, tetrahydropyran, tetrahydrothiopyran, etc.; etc.), etc., and the number of the substituents is preferably 1-3.
Examples of the substituent, which the xe2x80x9coptionally substituted lower (C1-4) alkylxe2x80x9d, the xe2x80x9coptionally substituted lower (C1-4) alkoxyxe2x80x9d, the xe2x80x9coptionally substituted phenyl|xe2x80x9d, the xe2x80x9coptionally substituted mono- or di-phenyl-lower (C1-4) alkylxe2x80x9d, the xe2x80x9coptionally substituted C3-7 cycloalkylxe2x80x9d and the xe2x80x9coptionally substituted heterocyclic ring groupxe2x80x9d as a substituent for said xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), an optionally halogenated lower (C1-4) alkyl, an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.) C2-4 alkanoyl (e.g. acetyl, propionyl, etc.). C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), C1-3 alkylenedioxy (e.g. methylenedioxy, ethylenedioxy, etc.). cyano, nitro, hydroxy group, thiol group, amino group, carboxyl group, lower (C1-4) alkoxy-carbonyl, etc., and the number of the substituents are preferably 1 to 3.
In the above formula (I), preferred example of the substituents for the xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d in the xe2x80x9coptionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammoniumxe2x80x9d include (1) halogen, (2) cyano, (3) hydroxy group, (4) carboxyl group, (5) lower (C1-4) alkoxy-carbonyl, (6) lower (C1-4,) alkyl which may be substituted with halogen, hydroxy group or lower (C1-4) alkoxy, (7) lower (C1-4) alkoxy which may be substituted with halogen, hydroxy group or lower (C1-4) alkoxy, (8) phenyl which may be substituted with halogen, lower (C1-4) alkyl, hydroxy group, lower (C1-4) alkoxy or C1-3 alkylenedioxy, (9) mono- or di-phenyl-lower (C1-4) alkyl whose benzene ring may be substituted with halogen, lower (C1-4) alkyl, hydroxy group, lower (C1-4) alkoxy or C1-3alkylenedioxy, (10) 5- to 6-membered aromatic heterocyclic ring such as furan, thiophene, pyrrole, pyridine, etc., etc.
In the above formula (I), examples of the xe2x80x9cgroup binding through a sulfur atomxe2x80x9d represented by R2 include a group of the formula: xe2x80x94S(O)mxe2x80x94Rs wherein m is an integer of 0-2, and Rs is a substituent.
In the above formula, preferred examples of the xe2x80x9csubstituentxe2x80x9d represented by Rs include
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(4) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.) etc.
Examples of the substituent, which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted aralkyl and (4) an optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula (I), examples of the xe2x80x9chydrocarbon groupxe2x80x9d in the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R5 and R6 of the xe2x80x9cgroup of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5 and R6 are independently an optionally substituted hydrocarbon group or an optionally substituted amino group, and R5 and R6 may bind to each other to form a cyclic group together with the adjacent phosphorus atomxe2x80x9d represented by R2 include
(1) an optionally substituted alkyl.(e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower (C2-6) alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted alkynyl (e.g. C2-10 alkynyl such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-pentynyl, 3-hexynyl, etc., preferably lower (C2-6) alkynyl, etc.);
(6) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(7) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc.
Examples of the substituents, which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted alkynyl, (6) optionally substituted aralkyl and (7) optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
Examples of the optionally substituted amino group represented by R5 and R6 include an amino group which may have 1-2 substituents selected from
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower (C2-6)alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc., etc.);
(5) an optionally substituted acyl (e.g. C2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(6) an amino group which may have 1-2 optionally substituted aryl groups (e.g. phenyl, naphthyl, etc.); etc.
Examples of the substituent, which the above mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted acyl and (6) optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula, the groups R5 and R6 may bind to each other to form a cyclic group (preferably, 5- to 7-membered ring) together with the adjacent phosphorus atom. Said cyclic group may have a substituent. Examples of the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula (I), examples of the counter anion, when the phosphorus atom forms a phosphonium, include an anion of a halogen atom (e.g. Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.), etc., and also an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc. are preferable.
As the group R2, (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium, (2) an optionally substituted nitrogen-containing heterocyclic ring group which may contain a sulfur atom or an oxygen atom as ring constituting atoms and wherein a nitrogen atom may form a quaternary ammonium, (3) a group of the formula: 
wherein R5 and R6 are independently an optionally substituted hydrocarbon group, and R5 and R6 may bind to each other to form a cyclic group together with the adjacent phosphorus atom, etc. are preferable.
In the above formula (Ixe2x80x2), examples of the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R5xe2x80x2 and R6xe2x80x2 in the xe2x80x9cgroup of the formula: 
wherein k is 0 or 1, and when k is 0, a phosphorus atom may form a phosphonium; and R5xe2x80x2 and R6xe2x80x2 are independently an optionally substituted hydrocarbon group, an optionally substituted hydroxy group or an optionally substituted amino group, and R5xe2x80x2 and R6xe2x80x2 may bind to each other to form a cyclic group together with the adjacent phosphorus atomxe2x80x9drepresented by R2 include those exemplified as the xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d and the xe2x80x9coptionally substituted amino groupxe2x80x9d represented by R5 and R6xe2x80x2, respectively.
In the above formula (Ixe2x80x2), examples of the xe2x80x9coptionally substituted hydroxy groupxe2x80x9d represented by R5xe2x80x2 and R6xe2x80x2 include a hydroxy group which may have
(1) an optionally substituted alkyl (e.g. C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably lower (C1-6 ) alkyl, etc.);
(2) an optionally substituted cycloalkyl (e.g. C3-7 cycloalkyl, etc. such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.);
(3) an optionally substituted alkenyl (e.g. C2-10 alkenyl such as allyl, crotyl, 2-pentenyl,3-hexenyl, etc., preferably lower (C2-6)alkenyl, etc.);
(4) an optionally substituted cycloalkenyl (e.g. C3-7 cycloalkenyl, etc. such as 2-cyclopentenyl, 2-cyclohexenyl, 2-cyclopentenylmethyl, 2-cyclohexenylmethyl, etc.);
(5) an optionally substituted aralkyl (e.g. phenyl-C1-4 alkyl (e.g. benzyl, phenethyl, etc.), etc.);
(6) an optionally substituted acyl (e.g. C2-4 alkanoyl (e.g. acetyl, propionyl, butyryl, isobutyryl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc.);
(7) an optionally substituted aryl (e.g. phenyl, naphthyl, etc.); etc.
Examples of the substituents, which the above-mentioned (1) optionally substituted alkyl, (2) optionally substituted cycloalkyl, (3) optionally substituted alkenyl, (4) optionally substituted cycloalkenyl, (5) optionally substituted aralkyl, (6) optionally substituted acyl and (7) optionally substituted aryl may have, include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula, the groups R5xe2x80x2 and R6xe2x80x2 may bind to each other to form a cyclic group (preferably, 5- to 7-membered ring) together with the adjacent phosphorus atom. Said cyclic group may have a substituent. Examples of the substituent include halogen (e.g. fluorine, chlorine, bromine, iodine, etc.), nitro, cyano, hydroxy group, thiol group, amino group, carboxyl group, an optionally halogenated C1-4 alkyl (e.g. trifluoromethyl, methyl, ethyl, etc.), an optionally halogenated C1-4 alkoxy (e.g. methoxy, ethoxy, trifluoromethoxy, trifluoroethoxy, etc.), C2-4 alkanoyl (e.g. acetyl, propionyl, etc.), C1-4 alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.), etc., and the number of the substituents are preferably 1 to 3.
In the above formula (Ixe2x80x2), examples of the counter anion, when the phosphorus atom forms a phosphonium, include an anion of a halogen atom (e.g. Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc.), etc., and also an anion derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; an anion derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.; an anion derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, Clxe2x88x92, Brxe2x88x92, Ixe2x88x92, etc. are preferable.
As the group R2, (1) an optionally substituted amino group in which a nitrogen atom may form a quaternary ammonium is preferable, and a group of the formula: xe2x80x94N+RRxe2x80x2Rxe2x80x3 wherein R, Rxe2x80x2 and Rxe2x80x3 are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic ring group is more preferable.
Among the Compound (I), a compound of the formula: 
wherein R1 is an optionally substituted benzene or an optionally substituted thiophene; Yxe2x80x3 is xe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94Oxe2x80x94; and R, Rxe2x80x2 and Rxe2x80x3 are independently an optionally substituted aliphatic hydrocarbon group or an optionally substituted alicyclic heterocyclic ring group is preferable.
Examples of the xe2x80x9coptionally substituted aliphatic hydrocarbon groupxe2x80x9d and the xe2x80x9coptionally substituted alicyclic heterocyclic ring groupxe2x80x9d represented by R, Rxe2x80x2 or Rxe2x80x3 include those exemplified by the substituents for the xe2x80x9coptionally substituted aminoxe2x80x9d represented by R2. Among them, as the group R or Rxe2x80x2, an optionally substituted acyclic hydrocarbon group is preferable, an optionally substituted C1-6 alkyl group is more preferable, and methyl is most preferable; and as the group Rxe2x80x3, an optionally substituted alicyclic hydrocarbon group (more preferably, an optionally substituted C3-8 cycloalkyl group; further more preferably, an optionally substituted cyclohexyl) or an optionally substituted alicyclic heterocyclic ring group (more preferably, an optionally substituted saturated alicyclic heterocyclic ring group (preferably 6-membered ring group); further more preferably, an optionally substituted tetrahydropyranyl, an optionally substituted tetrahydrothiopyranyl or an optionally substituted piperidyl; most preferably, an optionally substituted tetrahydropyranyl) is preferable.
Among the Compound (I), a compound of the formula: 
wherein Xxe2x88x92 is an anion is preferable.
Examples of the anion include that of a halogen atom; that derived from an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.; that derived from an organic acid such as formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc.; that derived from an acidic amino acid such as aspartic acid, glutamic acid, etc.; etc. Among others, an anion of a halogen atom is preferable.
Among the Compound (I), the following compounds and their salts are preferable:
N-methyl-N-[4-[[[2xe2x80x94(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]piperidinium iodide;
N-methyl-N-[4-[[[7xe2x80x94(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]piperidinium iodide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7xe2x80x94(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide;
N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-7xe2x80x94(4-morpholinophenyl)-2,3-dihydro-1-benzoxepine-4-carboxmide;
7xe2x80x94(4-ethoxyphenyl)-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxmide;
N,N-dimethyl-N-[4-[[[2xe2x80x94(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino benzyl]-N-(tetrahydropyran-4-yl)ammonium iodide;
N,N-dimethyl-N-[4-[[[7xe2x80x94(4-methylphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]-N-(4-oxocyclohexyl)ammonium chloride;
N,N-dimethyl-N-[4-[[[7xe2x80x94(4-ethoxyphenyl)-2,3-dihydro-1-benzoxepin-4-yl]carbonyl]amino]benzyl]-N-(tetrahydropyran-4-yl)ammonium chloride;
N-methyl-N-[4-[[[7xe2x80x94(4-methylphenyl)-3,4-dihydronaphthalen-2-yl]carbonyl]amino]benzyl]piperidinium iodide; etc.
Examples of the salts of the compound represented by the formula (I) [including the formula (Ixe2x80x2)] include a pharmaceutically acceptable salt such as a salt with inorganic base, a salt with organic base, a salt with inorganic acid, a salt with organic acid, a salt with basic or acidic amino acid, etc. Examples of the salt with the inorganic base include a salt with alkali metal (e.g. sodium, potassium, etc.), alkaline earth metal (e.g. calcium, magnesium, etc.), aluminum, ammonium, etc. Examples of the salt with the organic base include a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,Nxe2x80x2-dibenzylethylenediamine, etc. Examples of the salt with the inorganic acid include a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Examples of the salt with the organic acid include a salt with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, etc. Examples of the salt with the basic amino acid include a salt with arginine, lysine, ornithine, etc. Examples of the salt with the acidic amino acid include a salt with aspartic acid, glutamic acid, etc.
The compound of the formula (I) [including the formula (Ixe2x80x2)] of the present invention may be hydrated or solvated. When the compound of the formula (I) [including the formula (Ixe2x80x2)] of the present invention exists as configuration isomer, diastereomer, conformer, etc., it is possible to isolate individual isomers with per se known separation and purification method, if desired. When the compound of the formula (I) [including the formula (Ixe2x80x2)] of the present invention is racemate, it can be separated into (S)-compound and (R)-compound With usual optical resolution and individual optical isomers and a mixture thereof are included in the scope of the present invention.
The present compound of the formula (I) or a salt thereof (hereinafter, xe2x80x9cCompound (I)xe2x80x9d include the compound of the formula (I) and its salt; and also a compound of the formula (Ixe2x80x2) and its salt) alone or as an admixture with a pharmaceutically acceptable carrier (e.g. solid formulations such as tablets, capsules, granules, powders, etc.; liquid formulations such as syrups, injections, etc.) may be orally or non-orally administered.
Examples of non-oral formulations include injections, drops, suppositories, pessaryies, etc.
Examples of the carriers include various organic or inorganic carriers which are generally used in this field. For example, an excipient, a lubricant, a binder, an disintegrating agent, etc. are used in the solid formulations, and a solvent, a solubilizer, a suspending agent, a isotonizing agent, a buffer, a soothing agent, etc. are used in the liquid formulations. In addition, if desired, an appropriate additive such as a preservative, an antioxidant, a colorant, a sweetener, etc. may be used in the above formulations.
Examples of the excipient include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light silic acid anhydride, etc. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica, etc. Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, etc. Examples of the disintegrating agent include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, etc. Examples of the solvent include water for injection, alcohol, propyleneglycol, macrogol, sesame oil, corn oil, etc. Examples of the solubilizer include polyethyleneglycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, etc. Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium laurylsulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzetonium chloride, glycerin monostearate, etc.; hydrophilic polymers such as polyvinylalcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.; etc. Examples of the isotonizing agent include sodium chloride, glycerin, D-mannitol, etc. Examples of the buffer include a buffer solution of phosphate, acetate, carbonate, citrate, etc. Examples of the soothing agent include benzylalcohol, etc. Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc. Examples of the antioxidant include sulfites, ascorbic acid, etc.
The present invention is further to provide a production method of a compound of the formula (I) or a salt thereof.
The compound of the formula (I) or a salt thereof can be produced in accordance with per se known methods, for example, the methods described below, the methods described in JP-A-73476/1996, or analogous methods thereto.
A salt of the compound of the formulas (I), (II), (III), (IV), (V), (I-1), (I-2) and (I-3) may be similar to that of the compound the formula (I).
In the following reaction steps, when the starting compounds have, as substituents, an amino group, a carboxyl group and/or hydroxy group, these groups may be protected by ordinary protective groups such as those generally employed in peptide chemistry, etc. After the reaction, if necessary, the protective groups may be removed to obtain the desired compound.
Examples of the amino-protective group include an optionally substituted C1-6 alkylcarbonyl (e.g. formyl, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, C1-6 alkyloxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), aryloxycarbonyl (e.g. phenoxycarbonyl, etc.), C7-10 aralkyloxycarbonyl (e.g. benzyloxycarbonyl, etc.), trityl, phthaloyl, etc. These protective groups may be substituted by 1 to 3 substituents such as halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkylcarbonyl (e.g. acetyl, propionyl, butyryl, etc.), nitro group, etc.
Examples of the carboxyl-protective group include an optionally substituted C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl,tert-butyl, etc.), phenyl, trityl, silyl, etc. These protective groups may be substituted by 1 to 3 substituents such as halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkylcarbonyl (e.g. formyl, acetyl, propionyl, butyryl, etc.), nitro group, etc.
Examples of the hydroxy-protective group include an optionally substituted C1-6 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, C7-10 aralkyl (e.g. benzyl, etc.), C1-6 alkylcarbonyl (e.g. formyl, acetyl, propionyl, etc.), phenyloxycarbonyl, C7-10 aralkyloxycarbonyl (e.g. benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. These protective groups may be substituted by 1 to 4 substituents such as halogen atom (e.g. fluorine, chlorine, bromine, iodine, etc.), C1-6 alkyl, phenyl, C7-10 aralkyl ,nitro group, etc.
These protective group may be introduced or removed by per se known methods (e.g. a method described in Protective Groups in Organic Chemistry (J. F. W. McOmie et al.; Plenum Press Inc.) or the methods analogous thereto. For example, employable method for removing the protective groups is a method using an acid, a base, reduction, ultraviolet ray, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc. 
herein each symbol is as defined above.
This production method is carried out by reacting the compound [II] with the aniline derivative [III] to obtain the anilide Compound [I-1].
The condensation reaction of the compounds [III] and [III] is carried out by usual methods for peptide synthesis. Said methods for peptide synthesis are employed according to optional known methods, for example, methods described in xe2x80x9cPeptide Synthesisxe2x80x9d written by M. Bodansky and M. A. Ondetti, Interscience, New York, 1966; xe2x80x9cThe Proteinsxe2x80x9d, volume 2, written by F. M. Finn and K. Hofmann, H. Nenrath and R. L. Hill edition, Academic Press Inc., New York, 1976; xe2x80x9cpeputido-gosei no kiso to jikken (Basis and Experiment of Peptide Synthesis)xe2x80x9d written by Nobuo Izumiya et al., Maruzen K.K.,1985; etc., as well as azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, method using Woodward reagent K, carbonyldiimidazole method, oxidation-reduction method, DCC/HONB method, etc. and in addition WSC method, method using diethyl cyanophosphate (DEPC), etc.
The condensation reaction can be carried out in a solvent. Examples of the solvents to be employed in the reaction include anhydrous or hydrous N,N-dimethylformamide (DMF), dimethylsulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran, dioxane, acetonitrile, or a suitable mixture of these solvents. The reaction temperature is generally about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x9210xc2x0 C. to about 30xc2x0 C. and the reaction time is generally about 1 to about 100 hours, preferably about 2 to about 40 hours.
The thus obtained anilide derivative [I-1] can be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, recrystallization, solvent convert, chromatography, etc. 
{circle around (1)} When the group R2xe2x80x3 in Compound [I-2] is, for example, a tertiary amine residue, Compound [I-1] wherein the group R2xe2x80x2 is an quaternary ammonium can be produced by reacting Compound I-2] with halogenated alkyl or halogenated aralkyl. Examples of a halogen atom include chlorine, bromine, iodine, etc. and usually about 1 to 5 moles of the halogenated alkyl (e.g. halogenated lower (C1-6) alkyl, etc.) or halogenated aralkyl (e.g. halogenated lower (C1-4) alkyl-phenyl, etc.) is used per mole of Compound [I-2]. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylacetamide, etc., or a suitable mixture of these solvents. The reaction temperature is generally about 10xc2x0 C. to about 160xc2x0 C., preferably about 20xc2x0 C. to about 120xc2x0 C. and the reaction time is generally about 1 hour to about 100 hours. preferably about 2 hours to about 40 hours. This reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
{circle around (2)} When the group R2xe2x80x3 in Compound [I-2] is, for example, a secondary amine residue, Compound (I-1] wherein the group R2xe2x80x2 is a tertiary amino can be produced by reacting Compound [I-2] with halogenated alkyl or halogenated aralkyl. Examples of a halogen atom include chlorine, bromine, iodine, etc. and usually about 1 to 2 moles of the halogenated alkyl or halogenated aralkyl is used per mole of Compound [I-2]. If necessary, the reaction smoothly proceeds by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and further sodium iodide, potassium iodide, etc.
This tertiary amination reaction is carried out in an inert solvent such as methanol ,ethanol, propanol, isopropanbl, n-butanol, tetrahydrofuran, diethylether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylsulfoxide (DMSO), pyridine, etc., or a suitable mixture of these solvents. The reaction temperature is generally about 0xc2x0 C. to 180xc2x0 C., and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
{circle around (3)} When the group R2xe2x80x3 in Compound [I-2] is, for example, a secondary amine residue, Compound [I-1] wherein the group R2xe2x80x2 is a tertiary amino can be produced by reacting Compound [I-2] with aldehyde compound in the presence of a reductive amination reagent such as triacetoxysodium boron hydride, cyanosodium boron hydride, sodium boron hydride, etc.
The conditions of this reductive amination reaction varies depending on the reagent to be used. For example, when triacetoxysodium boron hydride is used reaction is carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, diethylether, dioxane, acetonitrile, dimethylformamide (DMF), etc., or a suitable mixture of these solvents. In this case, about 1 to 2 moles of the reagent is used per mole of Compound [I-2]. The reaction temperature is generally about 0xc2x0 C. to about 80xc2x0 C., and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
{circle around (4)} When the group R2xe2x80x2 in Compound [I-2] is, for example, a sulfide residue or a tertiary amine residue, Compound [I-1] wherein the group R2xe2x80x2 is a sulfinyl group, a sulfonyl group or an amine oxide group can be produced by reacting Compound [I-2] with an oxidizing agent such as m-chloroperbenzoic acid, perbenzoic acid, p-nitroperbenzoic acid, magnesium monoperoxyphthalate, peracetic acid, hydrogen peroxide, sodium periodate, potassium periodate, etc. The conditions of this oxidation reaction varies depending on the oxidizing agent to be used. For example, when m-chloroperbenzoic acid is used, reaction is carried out in an inert solvent such as dichloromethane, chloroform, 1,2-dichloroethane, diethylether, tetrahydrofuran, acetone, ethyl acetate, etc., or a suitable mixture of these solvents. Usually, about 1-3 moles of oxidizing agent is used per mole of Compound [I-2]. The reaction temperature is generally about xe2x88x9225xc2x0 C. to about 80xc2x0 C. (preferably xe2x88x9225xc2x0 C. to 25xc2x0 C.), and the reaction time is generally about 1 hour to about 40 hours. 
wherein V in the Compound [IV] is a halogen atom (chlorine, bromine, iodine, etc.), or a sulfonyloxy group (methane-sulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy group, toluenesulfonyloxy group, etc.), and the other symbols are as defined above.
{circle around (1)} Compound [I-1] wherein the group R2xe2x80x2 is a quaternary ammonium can be produced by reacting Compound [IV] and a tertiary amine. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF), dimethylacetamide, etc., or a suitable mixture of these solvents. Usually, about 1-3 moles of the tertiary amine is used per mole of Compound [IV]. The reaction temperature is generally about 10xc2x0 C. to about 120xc2x0 C., and the reaction time is generally about 1 hour to about 40 hours. This reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
{circle around (2)} Compound [I-1] wherein the group R2xe2x80x2 is a quaternary phosphonium can be produced by reacting Compound [IV] and a tertiary phosphine. The reaction is carried out in an inert solvent such as toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, acetonitrile, dimethylformamide (DMF), or a suitable mixture of these solvents. Usually, about 1-2 moles of the tertiary phosphine is used per mole of Compound [IV]. The reaction temperature is generally about 20xc2x0 C. to about 150xc2x0 C., and the reaction time is generally about 1 hour to about 50 hours. This reaction is preferably carried out under inert gas (e.g. nitrogen, argon, etc.) atmosphere.
{circle around (3)} Compound [I-1] wherein the group R2xe2x80x2 is a secondary or tertiary amino group or a thio group can be produced by reacting Compound [IV] and primary or secondary amine compound or thiol compound. Usually, about 1 to 3 moles of the primary or secondary amine compound or the thiol compound is used per mole of Compound [IV]. If necessary, the reaction smoothly proceeds by addition of about once to thrice moles of a base such as triethylamine, diisopropylethylamine, pyridine, lithium hydride, sodium hydride, sodium methoxide, sodium ethoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and further sodium iodide, potassium iodide, etc. This substitution reaction is carried out in an inert solvent such as methanol, ethanol, propanol, isopropanol, n-butanol, tetrahydrofuran, diethylether, dimethoxyethane, 1,4-dioxane, toluene, benzene, xylene, dichloromethane, chloroform, 1,2-dichloroethane, dimethylformamide (DMF),dimethylsulfoxide (DMSO), pyridine, etc., or a suitable mixture of these solvents. The reaction temperature is generally about xe2x88x9210xc2x0 C. to about 180xc2x0 C., and the reaction time is generally about 1 hour to about 40 hours. The reaction is carried out preferably under inert gas (e.g. nitrogen, argon, etc.) atmosphere. 
wherein Vxe2x80x2 is a halogen atom (bromine, iodine, etc.) or a sulfonyloxy group (trifluoromethanesulfonyloxy group, etc.), and the other symbols are as defined above.
Compound [I-3] wherein the group R1xe2x80x2 is a 5- to 6-membered aromatic ring group can be produced by subjecting Compound [V] to, for example, Suzuki reaction [cross condensation reaction of aryl borate with e.g. aryl halide or aryloxytrifluoromethanesulfonate in the presence of palladium catalyst; A. Suzuki et al., Synth. Commun. 1981, 11, 513]. Usually, about 1-1.5 times moles of aryl borate is use d per mole of Compound [V].
Compound [II] used as a starting material can be produced by a known method (e.g. method described in JP-A-73476/1996, etc.) or the methods analogous thereto. For example, Compound [II] can be produced by a method described in the following Reaction Scheme I, a method described in the following Reference Examples or the methods analogous thereto. 
wherein R9 is a C1-4 alkyl group, Yxe2x80x3 is a divalent group, which does not contain a unsaturated bond and by which the ring B forms a 5- to 7-membered ring, and the other symbols are as defined above.
In this reaction, the compound of the formula [VI] is heated with a polyphosphoric acid, or Compound [VI] is converted to acid chloride with thionyl chloride, oxalyl chloride, phosphorous oxychloride. phosphorous pentachloride, etc., followed by subjecting the resulting acid chloride to usual Friedel-Crafts reaction and cyclizing the same to produce Compound [VII]. Compound [VII] is reacted with carbonate ester in the presence of a base to produce ketoester [VIII]. Compound [VIII] is subjected to reduction with catalytic hydrogenation or sodium boron hydride, etc. to produce Compound [IX]. Compound [IX] is subjected to dehydration and ester hydrolysis by per se known method to produce unsaturated carboxylic acid [II-1].
Compound [III] can be produced by a known method (e.g. method described in JP-A-73476/1996, etc.) or the methods analogous thereto. For example, Compound [III] can be produced by a method described in the following Reaction Scheme II, a method described in the following Reference Examples or the methods analogous thereto. 
The reduction of Compound [X] can be carried but per se known methods, for example, reduction with metal, reduction with metal hydride, reduction with metal hydride complex compound, reduction with diborane or substituted borane, catalytic hydrogenation, etc. That is, this reaction is carried out by treating Compound [X] with reduction agent. Examples of the reduction agent include metal such as reduced iron, zinc powder, etc.; alkali metal boron hydride (e.g. sodium boron hydride, lithium boron hydride, etc.); metal hydride complex compound such as aluminum lithium hydride, etc.; metal hydride such as sodium hydride etc.; organic tin compound (triphenyltin hydride, etc.), metal complex compound and metal salt such as nickel compound, zinc compound etc.; catalytic reduction agent using hydrogen and transit metal catalyst such as palladium, plutinum, rhodium, etc.; diborane; etc. Among others, as the reduction agent, catalytic reduction agent using hydrogen and transit metal catalyst such as palladium, plutinum, rhodium, etc.; reduced iron, etc. are preferable. The reaction is carried out in a solvent which does not affect the reaction. Examples of the solvent include benzene, toluene, xylene, chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethylether, tetrahydrofuran, dioxane, methanol, ethanol, propanol, isopropanol, 2-methoxyethanol, N,N-dimethylformamide, acetic acid, or a suitable mixture of these solvents, etc. The solvent is appropriately selected depending on kind of the reduction agent. The reaction temperature is generally about xe2x88x9220xc2x0 C. to about 150xc2x0 C., preferably about 0xc2x0 C. to about 100xc2x0 C., and the reaction time is generally about 1 to about 24 hours.
The resulting Compound [III] can be separated and purified with know separation and purification methods such as concentration, concentration under reduced pressure, extraction, crystallization, was recrystallized with, solvent conversion, chromatography, etc.
The compound of the formula (I) or a salt thereof of the present invention has potent antagonistic activity on MCP-1 receptor and therefore can be used for the treatment or prophylaxis of various inflammatory diseases, cardiac infarction, myocarditis, etc. in human and animals (e.g. mouse, rat, cat, dog, rabbit, bovine, swine, etc.). The compound of the formula (I) or a salt thereof of the present invention is low toxic and safely used as MCP-1 receptor antagonist (e.g. a medicament for the treatment or prophylaxis of cardiac infarction, myocarditis, etc.).
The dose per day of the compound of the formula (I) or a salt thereof varies depending on the condition and body weight of a patient, administration route, etc. Typical daily dose per adult patient (body weight: 50 Kg) for oral administration is about 5-1000 mg, preferably about 10-600 mg, and in particular about 15-150 mg, as active ingredient [the compound of the formula (I) or a salt thereof] and the compound of the formula (I) or a salt thereof is administered once or 2-3 times par day.